Influence of Genetic Polymorphisms of VKORC1 and CYP2C9 in Patients on Phenprocoumon Steady-State Dose Requirements

Abstract

The variants of the (Vitamin-K epoxid reductase subcomplex 1) VKORC1 and of cytochrome P450 2C9 (CYP2C9) genes are know to influence the steady state dose of the vitamin-K antagonist (VKA) phenprocoumon during oral anticoagulant therapy. We have analysed in detail the influence of the VCORC1 1173CC and 1173CT variants in combination with the CYP2C9 variants on the steady state dose of phenprocoumon. The weekly phenprocoumon dosage was calculated after a 3 to 6 months of stable anticoagulation by the international normalized ratio (INR) which had to be in a range from 2 to 3 in 114 patients. VKORC1 1173CC, CT, TT and CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 genotypes were determined using direct DNA sequencing and realtime PCR. Patients carrying VKORC1 1173CT and CYP2C9*1/*1 genotypes required a 33% lower steady state dose of phenprocoumon compared to VKORC1 1173CC and CYP2C9*1/*1 genotypes (p=0.0001). Patients with VKORC1 1173CC in combination with CYP2C9*1/*2, *1/*3 needed 10% and 34% lower steady state dose of phenprocoumon compared to the combination with CYP2C9*1/*1, respectively (p=0.0001). Patients carrying VKORC1 1173CT needed lower doses of phenprocoumon in combination with CYP2C9*1/*1 (−32%), *1/*2 (−29%), or *1/*3 (−33%), and VKORC1 1173TT in combination with CYP2C9*1/*3 (−44%) compared to VKORC1 1173CC combined with CYP2C9*1/*1 (all p<0.001). CYP2C9 variants did not influence the dose of carriers of VKORC1 1173CT gene. Both genotypes together influenced the phenprocoumon maintenance dosage in this naturalistic study design. Genotyping for CYP2C9 and VCORC1 therefore might be a suitable tool for dose individualization in patients at oral anticoagulant drug therapy.